bims-unfpre 2026-08-23 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2026–08–23
seven papers selected by
Susan Logue, University of Manitoba

Unconventional role of hydroxymethylglutaryl-CoA synthase 1 in driving pathogenic TH17 cell immunity and autoimmune diseases.
The UPR drives gametogenesis via an unexpected response, coordinating translation and ER structure.
Iron-endoplasmic reticulum-extracellular matrix axis regulates cancer cell invasion.
Calcineurin B-mediated Ca 2+ sensing translates stress signal intensity into the assembly of phase-separated condensates at PERK complexes.
Proteostasis Collapse Drives Effector Memory T Cells Re-expressing CD45RA (TEMRA) Generation in the Tumor Microenvironment.
Targeted nanomedicines for endoplasmic reticulum stress: organelle-resolved delivery, immune modulation, and genetic reprogramming.
TMEM97 links endoplasmic reticulum stress to hepatic stellate cell activation in experimental liver fibrosis: pharmacological attenuation by CT1812.

Sci Adv. 2026 Aug 21. 12(34): eaee4337

Unconventional role of hydroxymethylglutaryl-CoA synthase 1 in driving pathogenic TH17 cell immunity and autoimmune diseases.

Jie Sun, Yali Lei, Huanhuan Yang, Shu Li, Bing Wu.

T helper 17 (TH17) cells are heterogeneous and able to adopt pathogenic and non-pathogenic phenotypes. Identifying factors controlling pathogenic TH17 cells is of importance for their vital role in inflammation and immune-pathology. Here, we demonstrated that HMGCS1, a cholesterol biosynthesis precursor enzyme, was highly induced by inflammatory cytokines and preferentially expressed by pathogenic TH17 cells in vitro and in vivo. HMGCS1 specifically dictated pathogenic TH17 cell differentiation and augmented autoimmune diseases, yet it has no discernible effect on nonpathogenic TH17 cells. Unexpectedly, this role is independent of its canonical function in cholesterol metabolism but requires its catalytic Cys129 residue. Notably, HMGCS1 governs pTH17 cell generation and pathogenicity by leveraging an IRE1α-XBP1s-dependent ER stress response, which in turn transcriptionally activates the lineage-defining factor RORγt (encoded by Rorc). Mechanistically, HMGCS1 is located to the ER membrane, where it bound and stabilized IRE1α protein. This stabilization is achieved by preventing IRE1α's interaction with the E3 ubiquitin ligase MARCH5, thereby inhibiting its K48-linked ubiquitination and subsequent degradation. Moreover, interfering with HMGCS1 or the ER stress response in T cells impedes pTH17 immunity and mitigates autoimmune disease in vivo. Therefore, our work unveils a noncanonical axis in which HMGCS1 sustains ER stress to license pTH17 differentiation during autoimmune responses.

DOI: https://doi.org/10.1126/sciadv.aee4337
J Cell Biol. 2026 Oct 05. pii: e202509100. [Epub ahead of print]225(10):

The UPR drives gametogenesis via an unexpected response, coordinating translation and ER structure.

Constantine Bartolutti, Alena Lauren Bishop, Yanzhe Ma, Kelsey Van Dalfsen, Elçin Ünal, Marko Jovanovic, Gloria Ann Brar.

Stress responses, including the unfolded protein response (UPR), are commonly studied via induction with harsh exogenous stressors, leaving endogenous functions of these pathways less well understood. We found that the endogenous UPR that precedes meiosis in budding yeast is required for gamete production but diverges dramatically from previously defined UPR outputs, with only a few characterized UPR targets induced, and mildly. The role of this UPR can be replaced by increasing ER chaperones, reducing bulk translation, or impairing the machinery for protein translocation into the ER. ER integrity appears compromised in premeiotic cells lacking the UPR, as foci of reticulon proteins are seen and correlate strongly with an inability of cells to enter meiosis. These findings indicate that physiological UPR activation supports proteostasis and normal ER structure, preparing cells for meiotic entry by reducing the load of proteins that enter the ER. Overall, our study reveals surprising features of a physiological UPR induction that enables a cell-fate decision.

DOI: https://doi.org/10.1083/jcb.202509100
bioRxiv. 2026 Aug 03. pii: 2026.06.29.735430. [Epub ahead of print]

Iron-endoplasmic reticulum-extracellular matrix axis regulates cancer cell invasion.

Arun Asif, Kavya Panjwani, Kavya Nair, Percy Smith, Oruko Dancan, Isaiah Crosbourne, Joseph DeLuca, Taylor Humphrey, Ramon Bossardi Ramos, David T Corr, Teresita Padilla-Benavides, Margarida Barroso.

Intracellular iron homeostasis is increasingly recognized as a regulator of cancer cell behavior, but how iron distribution influences extracellular matrix (ECM) organization and invasion remains poorly understood. Here, we show that loss of divalent metal transporter 1 (DMT1/SLC11A2) disrupts intracellular iron homeostasis and promotes cancer cell invasion through an iron-ER-ECM axis. In MDA-MB-231 cells, DMT1 knockout (KO) reduced total iron content but increased the labile iron pool (LIP) in both 2D and 3D culture models, indicating altered intracellular iron distribution. Across transcriptomic and phenotypic readouts, DMT1-dependent effects were more evident in 3D than in 2D models, with DMT1 KO inducing endoplasmic reticulum (ER) stress and impaired collagen/ECM organization. Functionally, the DMT1-loss phenotype was marked by reduced 2D motility, whereas in 3D spheroid models DMT1 KO cells displayed enhanced invasive outgrowth in both Matrigel and collagen matrices. Iron chelation further modulated this phenotype in a DMT1-dependent manner. Pharmacologic induction of ER stress phenocopied the loose spheroid architecture and invasive behavior, supporting ER stress as a mechanistic link between altered iron handling and ECM destabilization. Together, these findings identify intracellular iron distribution, rather than total iron abundance alone, as a determinant of ECM integrity and context-dependent cancer cell invasion. One Sentence Summary: Iron misrouting, not iron excess, drives ER stress and collagen failure that unleash invasion in triple-negative breast cancer.

DOI: https://doi.org/10.64898/2026.06.29.735430
bioRxiv. 2026 Aug 04. pii: 2026.08.03.742535. [Epub ahead of print]

Calcineurin B-mediated Ca 2+ sensing translates stress signal intensity into the assembly of phase-separated condensates at PERK complexes.

Sebastian M Bairo, Macarena Fernandez, Gonzalo Quasollo, Andrea Pellegrini, Juan C de Batista, Santiago Asis, Mauricio Martin, Deborah Holstein, James D Lechleiter, Gabriela E Gomez, Mariano Bisbal, Mariana Bollo.

Endoplasmic reticulum (ER) stress activates protein kinase RNA-like ER kinase (PERK), which initially promotes adaptive responses but remains the only active UPR branch during prolonged stress, mediating both early cytoprotective and chronic pro-apoptotic signaling. Recently, we identified translocon-generated Ca 2+ microdomains that promote PERK phosphorylation during early UPR, revealing a mechanism by which local Ca 2+ signals regulate UPR activation. However, the molecular mechanism linking these Ca 2+ microdomains to PERK activation remains elusive. Previously, we showed that calcineurin (CN), a Ca 2+ -dependent heterodimer composed of catalytic (CNA) and regulatory (CNB) subunits, exerts a non-canonical pro-survival function by promoting PERK autophosphorylation. Here, using super-resolution microscopy, CRISPR-Cas9 editing, in silico analyses, and optogenetic droplet assays, we identify CNB as a local Ca 2+ sensor that couples translocon-generated Ca 2+ signals to liquid condensate assembly, thereby promoting adaptive PERK phosphorylation. These findings establish CNB-mediated condensate assembly as a mechanism that translates local Ca 2+ signals into spatially organized early adaptive PERK signaling.

DOI: https://doi.org/10.64898/2026.08.03.742535
Phenomics. 2026 Apr;6(2): 150-167

Proteostasis Collapse Drives Effector Memory T Cells Re-expressing CD45RA (TEMRA) Generation in the Tumor Microenvironment.

Linlin Li, Shuo Kan, Qiang Huang, Shiwen Wang, Yuchen Han, Liang Chen, Jun Jin.

  T cell senescence causes T cell dysfunction in tumors, but its drivers are unclear. Here we found that protein overload in the tumor microenvironment (TME) induces T cell differentiation into effector memory T cells re-expressing CD45RA (TEMRA). TEMRA cells exhibit senescent-like features, including reduced proliferative capacity and expression of senescence-associated markers. Both CD4+ and CD8+ T cells activated under high protein-to-amino-acid-ratio conditions in vitro or within TME niches underwent enhanced TEMRA differentiation. Single-cell transcriptomics showed that protein overload co-activates terminal effector and senescence programs. Mechanistically, it disrupts proteostasis by inhibiting lysosomal and proteasomal degradation, triggering a maladaptive unfolded protein response (UPR) that drives TEMRA commitment. Exogenous amino acid supplementation prevented UPR activation and TEMRA differentiation. In humanized tumors, intra-tumoral amino-acid administration reduced TEMRA accumulation, boosted T cell proliferation, and improved tumor control. Our work reveals managing proteostatic stress as a strategy to counter TEMRA generation and restore anti-tumor immunity.
Supplementary Information: The online version contains supplementary material available at 10.1007/s43657-025-00309-7.

Keywords:  Cellular proteostasis; Effector memory T cells re-expressing CD45RA; Protein overload; Tumor microenvironment

DOI:  https://doi.org/10.1007/s43657-025-00309-7
Nanoscale. 2026 Aug 17.

Targeted nanomedicines for endoplasmic reticulum stress: organelle-resolved delivery, immune modulation, and genetic reprogramming.

Huanli Zhou, Sijie Wang, Songgela Nuerboli, Xuemeng Guo, Lihua Luo, Jian You.

Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) operate as central signaling hubs that integrate cellular homeostasis, adaptation, and fate determination. Dysregulation of this network constitutes a common pathogenic thread across cancer, metabolic syndromes, neurodegeneration, and inflammatory disorders. Although small molecule ERS modulators have validated the therapeutic relevance of this axis, their clinical translation remains constrained by intrinsic pharmacokinetic limitations, including poor solubility, off-tissue distribution, and an inability to synchronize drug action with the fluctuating dynamics of ERS. Nanotechnology is now catalyzing a paradigm shift by which engineered nanocarriers do not merely deliver ERS-targeting agents more efficiently; they unlock entirely new modalities of ERS intervention. By integrating stimuli-responsive motifs responsive to pH, reactive oxygen species, or enzymes, nanocarriers enable spatiotemporally programmable release that aligns therapeutic action with disease microenvironments. Through surface engineering and subcellular tropism, they achieve organelle-resolved ERS calibration, directing cargoes to the endoplasmic reticulum, mitochondria, or Golgi apparatus to modulate stress at its source. Beyond subcellular compartments, nanocarriers can also be tailored to target specific immune subsets, enabling precise modulation of ERS in dendritic cells, macrophages, and T lymphocytes. This emerging capability provides a means to reshape antigen presentation, inflammatory polarization, and effector functions, thereby linking ERS biology to cancer immunotherapy, autoimmune regulation, and infectious disease control. When integrated with epigenetic modulation, nanocarrier-mediated co-delivery of genetic and epigenetic agents offers a convergent strategy to simultaneously reprogram UPR signaling and correct epigenetic aberrations, thereby achieving superior therapeutic outcomes in ERS-driven diseases compared with single-modality approaches. This review systematically dissects nanocarrier-enabled strategies for ERS modulation, with emphasis on their architectural innovations in drug delivery, molecular logic of intervention, and therapeutic applications across major disease models. We also discuss current barriers to clinical translation and highlight emerging directions for extending ERS-targeted interventions toward broader pathological contexts.

DOI: https://doi.org/10.1039/d6nr01043a
Eur J Pharmacol. 2026 Aug 19. pii: S0014-2999(26)00742-9. [Epub ahead of print]1033 179260

TMEM97 links endoplasmic reticulum stress to hepatic stellate cell activation in experimental liver fibrosis: pharmacological attenuation by CT1812.

Jing Li, Wei Liu, Hong Zhang, Jing Zhang, Fang Li.

  Liver fibrosis lacks broadly effective antifibrotic therapies, and activated hepatic stellate cells drive extracellular matrix deposition. We investigated whether transmembrane protein 97 (TMEM97), the σ-2 receptor, contributes to hepatic stellate cell (HSC) activation and whether the σ-2 receptor complex antagonist CT1812 attenuates experimental fibrosis. In male C57BL/6J mice, carbon tetrachloride (CCl4) was administered for 4 or 8 weeks, and a separate 8-week CCl4 model received daily oral CT1812 (10 mg/kg/day) or vehicle. Human LX-2 cells were stimulated with transforming growth factor-β1 (TGF-β1) and treated with TMEM97-targeting small interfering RNA (siTMEM97), CT1812, or both; confirmatory experiments used a second siRNA and GSK2606414. Hepatic TMEM97 mRNA, protein abundance, and fluorescence intensity increased progressively during CCl4-induced fibrosis and were preferentially associated with α-smooth muscle actin (α-SMA)-positive fibrotic cells. In LX-2 cells, TMEM97 knockdown and CT1812 reduced ACTA2, COL1A1, and CTGF expression and suppressed proliferation and migration without reducing cell viability over 72 h. Both interventions attenuated multiple unfolded protein response readouts, including p-eIF2α/eIF2α, ATF4, CHOP, BiP, nuclear ATF4, p-IRE1/IRE1, and ATF6 (p50). The second siRNA reproduced key phenotypes, while GSK2606414 reduced PERK-eIF2α signaling and fibrogenic readouts. In vivo, CT1812 reduced hepatic hydroxyproline accumulation, collagen staining, α-SMA and collagen I expression, ER-stress markers, liver-injury indices, inflammatory cytokines, and macrophage accumulation. These findings support TMEM97-associated σ-2 receptor complex signaling as a contributor to ER-stress-coupled HSC activation and identify CT1812 as a candidate pharmacological modulator of experimental liver fibrosis.

Keywords:  CCl(4); CT1812; Endoplasmic reticulum stress; Hepatic stellate cells; Liver fibrosis; TGF-β1; TMEM97; σ-2 receptor

DOI:  https://doi.org/10.1016/j.ejphar.2026.179260